DE4416433A1 - Cyclohexane derivatives, process for their preparation and the use of the compounds for the treatment of diseases - Google Patents

Abstract

Cyclohexane derivs. of formula (I), and their salts, are new. R<2> = O-(3-5C)alkyl-R<11>, in which the alkyl component is straight, branched or cyclic; R<11> = phenyl (opt. 4-substd. by F, Cl or Me); and R<4>, R<5> = H or OH.

Description

EP-A-0 587 088 relates to substituted cyclohexane derivatives of the formula A.

which inhibit the liver glucose-6-phosphatase system in mammals and therefore can be used as a medicine.

The different radicals in formula A have the following meanings:
R¹: CN, COOH, a COOH group protected with a protective group, C₁-C₄-alkanoyl, SO₃-C₁-C₄-alkyl, SO₃H, SO₂NR⁸R⁹, PO (OH) ₂, PO (OH) (O-C₁-C₄- Alkyl), PO (O-C₁-C₄-alkyl) ₂₁
R²: C₁-C₁₀-alkyl (R¹¹) _n , O-C₁-C₁₀-alkyl (R¹¹) _n , C₂-C₁₀-alkenyl (R¹¹) _n , O-C₃-C₁₀-alkenyl (R¹¹) _n , C₂-C₁₀- Alkynyl (R¹¹) _n , O-C₃-C₁₀-alkynyl (R¹¹) _n , S-C₁-C₁₀-alkyl (R¹¹ _n , S-C₃-C₁₀-alkenyl (R¹¹) _n , S-C₃-C₁₀-alkynyl (R¹¹ ) _n , NH-C₁-C₁₀-alkyl (R¹¹) _n , NH-C₃-C₁₀-alkenyl (R¹¹) _n or NH-C₃-C₁₀-alkynyl (R¹¹) _n , where R¹¹ is optionally substituted with R¹²;
R³, R¹¹ and R¹³: alkyl with 1 to 10 C atoms, cycloalkyl with 3-8 ring C atoms, phenyl, naphthyl, phenanthryl, pyridyl, thienyl, furyl, pyrimidyl, indolyl, imidazolyl, coumarinyl, phthaliminyl, quinolyl, Piperazinyl, tetrazolyl, triazolyl, oxazolyl or their thieno-, pyridino-, pyrimidino- or benzo-fused derivatives, the aromatic or heteroaromatic one or more times with F, Cl, Br, J, OH, CF₃, -NO₂₁ CN, C₁- C₄-alkoxy, C₁-C₄-alkyl, NR⁸R⁹, phenyl, benzyl, thienyl, furyl, imidazolyl, pyridyl, O-phenyl or O-benzyl may be identical or different, and R³, R¹¹ and R¹³ are identical or different;
R⁴, R⁵ and R⁶: H, OH, an OH group protected by conventional alcohol protecting groups, F, Cl, Br or the meanings given for R², where R⁴, R⁵ and R⁶ are identical or different;
R⁷: C₁-C₄ alkyl, phenyl or benzyl;
R⁸ and R⁹: H, C₁-C₄-alkyl, C₁-C₄-alkanoyl, phenyl, which is optionally substituted with F, Cl, Br, J, OH, O-C₁-C₄-alkyl, CF₃₁ -NO₂ or CN, wherein R⁸ and R⁹ are the same or different, or R⁸ and R⁹ together with the nitrogen atom form a 4 to 10-membered, saturated heterocyclic ring, in which a CH₂ group can optionally be replaced by O, S or NR¹⁰,
R¹⁰: H, C₁-C₄ alkyl, phenyl or benzyl,
R¹²: phenyl, naphthyl, phenanthryl, pyridyl, thienyl, furyl, pyrimidyl, indolyl, imidazolyl, coumarinyl, phthaliminyl, quinolyl, piperazinyl, tetrazolyl, triazolyl, oxazolyl or their thieno- or benzo-fused derivatives, where the aromatic or Heterarone or derivatives, with the aromatics or Heterarone several times with F, Cl, Br, J, OH, CF₃₁-NO₂, CN, C₁-C₄-alkoxy, C₁-C₄-alkyl, C₂-C₄-alkenyl, NR⁸R⁹, phenyl, benzyl, thienyl, furyl, imidazolyl, pyridyl, O-phenyl or O-benzyl may be substituted the same or different;

Y: (CH₂) m, O, S, NR⁸,
Z: (CH₂) m, S, O, S-C₁-C₁₀ alkyl, O-C₁-C₁₀ alkyl, CH = CH, CH = CF, CH = CCl, CH = CBr, CH₂-CO, CH₂-CHF , CH₂-CHCl, CH₂-CHBr,
CH₂-CHJ, C₃-C₁₀ cycloalkylene, C₃-C₁₀ cycloalkenylene, where 1 to 3 ring C atoms can be replaced by sulfur, oxygen or nitrogen atoms, COOR⁷, C≡C, CH = C (C₁-C₄ -Alkyl), CH = C (CN), CH = C (NR⁸R⁹), CH = C (C₁-C₄- alkanoyl), CH-C (R¹³), NR⁸ and when Y is oxygen, can

together an amino acid residue selected from the group consisting of Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Phe, Pro, Ser, Thr, Trp, Tyr and their usual protective groups protected derivatives,
n: zero, 1 or 2
m: zero, 1, 2, 3 or 4.

It has now been found, completely surprisingly, that compounds of the formula A which carry very special residues and are not described in EP-A-0 587 088 are an extremely strong inhibitory effect on glucose-6-phosphatase System of the liver in mammals.  

The invention therefore relates to cyclohexane derivative of the formula

wherein
R² is O-C₃-C₅-alkyl (R¹¹), the alkyl part being straight-chain, branched or cyclic and
R¹¹ phenyl, which is optionally substituted in the 4-position with fluorine, chlorine or methyl, and
R⁴ and R⁵ are the same or different and / or OH, and their physiologically tolerable salts.

The compounds of formula I according to the invention contain a number of Stereo centers. The invention relates to all possible enantio and Diastereomers. They are all represented by Formula I.

The effect of the compounds according to the invention on glucose-6 Phosphatase system was examined in an enzyme test in liver microsomes.

For the preparation of the microsome containing glucose-6-phosphatase Fraction fresh liver organs from male Wistar rats were used and processed as described in the literature [Canfield, W. K. and Arion, W. J., J. Biol. Chem. 263, 7458-7460, (1988)]. This microsome fraction can be at -70 ° C for at least 2 months without significant loss of activity be kept.  

The detection of glucose-6-phosphatase activity was as in the literature (Arion, W. J. in Methods Enzymol. 174, Academic Press 1989, page 58-67) by determining the phosphate released from glucose-6-phosphate carried out. 0.1 ml test batch contained glucose-6-phosphate (1 mmol / l), which Test substance, 0.1 mg microsome fraction and 100 mmol / l HEPES buffer (4- (2- Hydroxyethyl) piperazin-1-ethanesulfonic acid), pH 7.0. The reaction was through Addition of the enzyme started. After 20 minutes at room temperature the reaction was stopped by adding 0.2 ml of phosphate reagent. The Sample was incubated at 37 ° C for 30 min and the absorption (A) of the blue Color then measured at 570 nm. The inhibitory effectiveness of Test substance was found by comparison with a control reaction that did not Test substance contained according to the formula

If necessary, the inhibitory effect of the test substance became a function the concentration of the test substance used, and from this the Concentration for the 50% inhibition of enzyme activity (IC₅₀) calculated.

The IC₅₀ value was determined for the compounds listed below:

Example 1 IC₅₀

Example 2

Example 3

Example 4

Example 5

Example 6

Example 7

The compounds according to the invention thus issue a selection connection the compounds claimed in EP-A-0 587 088.  

The compounds of the formula I according to the invention are prepared analogously the process described in EP-A-0 587 088, where in the case R² = O-C₃-C₅-cycloalkyl (R¹¹) advantageously analogous to that in German Patent application P 44 13 402.9 proposed method for producing the Starting product is worked.

example 1 1. Preparation of the starting compound 1e

Stage a

2.95 g (0.0985 mol) of NaH, 80% strength, were added in portions to a solution of 5 l of anhydrous methanol and 1.5 l of anhydrous tetrahydrofuran under an argon atmosphere at room temperature. Subsequently, compound 1 (see EP-A-0 587 088) was also added as a solid at room temperature. A clear solution was obtained after 3-4 hours. For working up, 6.0 g of glacial acetic acid (pH ∼5) and then 2 l of water in portions were added. A flaky precipitate of unreacted lactone was formed, which could be filtered off without any problems. (Recovery of starting material!)
The filtrate was then concentrated until a thick white precipitate formed. The mixture was cooled with ice, the precipitate was filtered off and washed with ice-cold methanol / water 1: 1.

After drying the precipitate at 1 mbar and 40 ° C., 370 g (86%) of compound 1b were obtained as a colorless solid.
Mp .: 102-104 ° C

Stage b

384.0 g (0.879 mol) of alcohol 1 b from stage a became anhydrous in 1.3 l Dichloromethane dissolved. Then 10.74 g (0.0879 mol) 4-dimethylaminopyridine and 364.8 ml (2,637 mol) of anhydrous triethylamine admitted. The solution was cooled to 0-10 ° C. and 164.7 ml were added dropwise (1.418 mol) of benzoyl chloride dissolved in 350 ml of anhydrous dichloromethane. After 4 hours at room temperature, only traces of starting material were still present. TLC: ethyl acetate / cyclohexane 1: 2 The reaction product was added to 1.5 l of water / 400 g of NH4Cl / 1 l of ice. The mixture was then extracted twice with dichloromethane and washed once with saturated bicarbonate solution and dried the combined organic phases with Na₂SO₄. After concentration, the residue was made from isopropanol crystallized.

437.0 g (91.9%) of product 1c were obtained.
Mp .: 104-107 ° C.

Stage c

To 2 l of anhydrous dichloroethane (instead of dichloroethane, other Inert solvents (dichloromethane, toluene, THF) were used at 0 ° C under an argon atmosphere 80.5 ml (0.785 mol) of pure diethyl zinc (instead of pure diethyl zinc can 1 molar solution in toluene (Aldrich) can also be used) from a steel bomb using a Steel cannula overpressed.

114.4 ml (1.57 mol) of chloroiodomethane were then added dropwise at 0-10 ° C. stirred the resulting suspension for 30 minutes and then dripped 169.89 g (0.314 mol) of the olefin 1c from stage b, dissolved in 500 ml anhydrous dichloroethane, too. After 1 hour at 0-10 ° C this was left Warm the reaction mixture to room temperature and stir for a further 3 Hours at room temperature.  

The reaction mixture was slowly poured into a solution of 300 g NH4Cl / 1.5 l ice water under a nitrogen atmosphere and extracted with dichloromethane. The combined organic phases were shaken with saturated NaCl solution and dried with Na₂SO₄. The majority of the solvent was then concentrated in vacuo and diluted with isopropanol. Then it was narrowed further until a thick precipitate failed. This precipitate was filtered off with suction and recrystallized twice from isopropanol, giving 109.8 g (63%) of compound 1d with a DE <98%.
Mp: 143-144 ° C

Stage d

99.0 g (0.178 mol) of compound 1d from step c were in 1200 ml of dioxane dissolved and 890 ml of 2N sodium hydroxide solution were added. The suspension became 2nd Heated to 80 ° C for hours.

The reaction solution was cooled down to approx. 10 ° C. and 228 ml (2 moles) semi-conc. Glacial acetic acid slowly added dropwise (pH 5-6). Then the  Rotate the solution in until the first cloudiness appears. This concentrate was poured into approx. 1500 ml of water with vigorous stirring, from which after 10 Minutes of stirring, a crystalline precipitate precipitated out. This rainfall was suction filtered and dried in vacuo at 22 ° C and 0.5 bar.

82.2 g of compound 1e were obtained.

2. Preparation of the starting compound of formula 1 F

takes place analogously to the information in EP-A-0 587 088 according to the following Reaction scheme:

Representation of 1B from 1A:
162 g (1 mol) 1A are dissolved in 400 ml dichloromethane. 31.4 nl of bromine are added dropwise at 0-15 ° C. The mixture is stirred at 15 ° C. for 2 h and concentrated in vacuo. 261 g of 1B are obtained as a colorless solid.

Representation of 1D from 1B:
A mixture of 50 g of methyl 2,3-dibromo-3-phenylpropanoate 1B, 100 ml of triethylamine and 500 ml of toluene is heated to boiling for 1 h, then cooled to room temperature and filtered. The filtrate is evaporated in vacuo and the α-bromocinnamic acid 1C thus obtained is used without purification. 0.2 mol of imidazopyridine, dissolved in 150 ml of anhydrous DMF, are added dropwise to a suspension of 4.7 g of NaH (80% in mineral oil) in 100 ml of anhydrous DMF with stirring. The temperature of the mixture is kept below 35 ° C. by cooling with ice. When the addition is complete, the mixture is stirred at room temperature for 1 h. The a-bromocinnamic acid previously prepared is dissolved in 200 ml of anhydrous DMF and, while cooling with ice, the solution of the azole sodium salt is added dropwise with stirring. After stirring for two hours at room temperature, 10.8 ml of glacial acetic acid are added, the mixture is stirred into 1.5 l of ice water, extracted several times with ethyl acetate and the organic phases are washed with water. The organic phases are dried, evaporated in vacuo and the residue is crystallized from ethyl acetate. 37.0 g of 1D are obtained as light yellow crystals.

Representation of 1E from 1D:
27.0 g (0.097 mol) of 1D was dissolved in 200 ml of methanol. 100 ml of 2.5 N NaOH was added. This solution is stirred at 22 ° C. for 12 h. Then 200 ml of 2N acetic acid are added dropwise. The precipitate was filtered off and washed with ethyl acetate. 22.0 g of 1E are obtained as a colorless solid.

Representation of 1F from 1E:
9.2 g (34.7 mmol) 1E were dissolved in 170 nl dimethylformamide and 6.5 g (38.2 mmol) carbonylditriazole were added at 22 ° C. The suspension was heated at 50-60 ° C. for 1 hour and a clear yellow solution of 1F in dimethylformamide was obtained, which was used in the subsequent reaction without working up.

3. Manufacture of

from 1e and 1F
10.1 g (23.1 mmol) 1e are dissolved in 200 ml of anhydrous dimethylformamide and 2.08 g of 80% sodium hydride are added at 0-5 ° C. A suspension of the sodium salt forms to the 1.5 eq. be dropped into solution 1F at 0-5 ° C. After 1 h, the reaction solution is added to 2 N acetic acid. The mixture is extracted with ethyl acetate and the combined organic phases are dried with sodium sulfate. After concentration in vacuo, the residue is purified by chromatography on silica gel (mobile phase ethyl acetate / n-heptane / methanol / glacial acetic acid 8: 10: 1: 1). 5.6 g (8.19 mol) of 1f are obtained as a colorless viscous oil.

4. Establishing connection 1

Representation of 1 from 1f:
21.0 g of 1f are dissolved in 300 ml of dioxane and 75 ml of 2N HCl are added. This solution is heated to 50-60 ° C for 2 1/2 hours and then cooled back to 20 ° C. 135 ml of 1N sodium hydroxide solution are then added dropwise (pH 3). The dioxane is distilled off in vacuo and an aqueous suspension is obtained. The precipitate is suctioned off. 13.8 g of 1 are obtained as a colorless solid.
Mp 158-160 ° C

The following compounds were prepared in an analogous manner.  

Example 2

MS: m / z = 592 (M + H⁺)

Example 3

Mp: 132-135 ° C

Example 4

MS: m / z = 583 (M + H⁺)  

Example 5

MS: m / z = 618 (M + H⁺)

Example 6

m / z = 576 (M + H⁺)

Example 7

m / z = 572 (M + H⁺)

Claims (6)

1. Cyclohexane derivatives of the formula I. wherein
R² is O-C₃-C₅-alkyl (R¹¹), the alkyl part being straight-chain, branched or cyclic and
R¹¹ phenyl, which is optionally substituted in the 4-position with fluorine, chlorine or methyl, and
R⁴ and R⁵ are the same or different and are H or OH, and their physiologically tolerable salts. 2. Use of compounds according to claim 1 for the treatment of Diseases associated with increased glucose-6-phosphatase activity Systems are connected. 3. Use of compounds according to claim 1 for the treatment of Diseases associated with increased liver glucose production are. 4. Use of compounds according to claim 1 for the treatment of the type II diabetes (non-insulin dependent or adult diabetes).   5. Use of compounds according to claim 1 for the preparation of Medicines to treat type II diabetes and other diseases that due to increased glucose output from the liver or increased activity of the glucose-6-phosphatase system. 6. Medicament containing a compound according to claim 1.